Tape cast multi-layer ceramic/metal composites

ABSTRACT

The invention described herein is a bioactive composite material comprising thin layers of bioactive glass reinforced with thin ductile metallic layers, and the use of this material in bone replacement procedures.

This is a continuation of Ser. No. 09/216,510 filed Dec. 18, 1998 nowU.S. Pat. No. 6,306,925 which claims of No. 60/068,174 filed Dec 19,1997.

BACKGROUND OF THE INVENTION

Natural (autogenic and allogenic) bone tissue is commonly used for bonereplacement to correct defects caused by disease or trauma. However,natural bone tissue is not available in sufficient quantities to meetthe growing demand. Further, there is a risk of viral infectionassociated with the use of transplanted tissue. Synthetic materialscurrently available are limited by inadequate mechanical properties,poor implant-tissue interfacial bonding, or both. Initial implantstability is enhanced if the implant is able to rapidly bond to thesurrounding tissue. New orthopaedic synthetic biologically activematerials are needed which are readily available and have bonding andmechanical properties comparable to that of natural bone tissue.

The major mineral phase in bone, hydroxyapatite (“HA”), which has thechemical formula: Ca₁₀(PO₄)₆(OH)₂, is able to slowly bond with bone invivo. By contrast, the inert metals, such as stainless steel andtitanium, used in the construction of implanted orthopaedic devices arenot generally considered to bond to bone or soft tissue and aregenerally attached by mechanical means such as pins and screws. In manycases, it would be desirable for the devices to bond to body tissue.That is, material from which the devices were constructed should bebiologically active, i.e. “bioactive.” Thus, researchers have focused ondeveloping HA coatings for orthopaedic implants which would allow theimplants to become bound to body tissue. Unfortunately, the bond whichforms between HA and metal implants is weak and subject to fracture.Also, the long term effects of HA coatings relative to uncoated,mechanically bound prostheses are unknown.

The bioactivity index is a measure of the time required for greater than50% of the interface of a material with bone to become bonded to thebone. The bioactivity index of hydroxyapatite is 3.1. In comparison, theindexes for certain biologically active glasses composed of SiO₂, Na₂O,CaO and P₂O₅, “bioactive glasses” as they are known, are significantlyhigher. For example, for the particular bioactive glass, 45S5 BIOGLASS®,the index is reported to be 12.5. Bioactive glasses when exposed toaqueous solution, e.g., simulated body fluid or water, the outer silicalayer becomes hydrated and serves as a nucleation site for precipitationof amorphous calcium phosphate, which becomes crystalline with time.Silicon ions released form the hydrated layer appear to enhance theproliferation of osteoblasts, the cells which build bone. Thus, whenimmobilized against bone for two weeks 45S5 BIOGLASS® forms aninterfacial bond as strong as the bone itself. [Filho, O. P. LaTorre, G.P. and Hench, L. L. (1996). “Effect of Crystallization on apatite-layerformation bioactive glass 45S5, J. Biom. Mater. Res. 30, 509-514.]

Although bioactive glass has a significant advantage over hydroxyapatitebecause it is able to rapidly bond to bone and soft tissue, itsmechanical properties are insufficient to allow it to be used forload-bearing applications including use as a bonding medium for implantsand for extensive bone replacement. For example, researchers haveattempted to coat metallic implants with bioactive glass in efforts toimpart the surface with the ability to bond with bone and surroundingtissue. However, the metal-glass bond was not strong enough to bepractical. Thus, significant improvement of the mechanical properties ofbioactive glasses was needed to meet the demands of load bearingapplications.

Attempts to produce laminate composites with (a) high strain to failureand (b) a bioactive coating have been disappointing. Development of abioactive laminate with flexural strength (100 MPa) and strain tofailure equal to that of bone (8%) would be of clinical significance.

The use of bioactive ceramics and glass in polymer composites is knownin the art (see, for example, U.S. Pat. Nos. 5,017,627 and 5,728,753 toBonfield et al.). These patents teach the use of a dispersed phase of abioactive material, either bioactive glass, or hydroxyapatite, in apolyolefinic matrix. These materials are limited in their ultimatetensile strength, and do not possess the fracture toughness necessary tobe a fully weight-bearing bone implant. The dispersed phase, whether aparticulate or a fiber, can act as a stress-riser, which limits theuseful mechanical properties of the material. In addition, they onlyhave a percentage of bioactive material at their surface. It would beadvantageous to provide materials with a bioactive surface whichincreases the bone and soft tissue bonding ability of the material,while gaining significant tensile strength properties and fracturetoughness higher than conventional bloactive composite materials.

SUMMARY OF THE INVENTION

An aspect of the present invention is a bioactive bone replacementcomposite material comprising bioactive glass reinforced with one ormore ductile metallic layers. Preferably, the composite includes atleast two ductile metallic layers and has a flexural strength equal toor greater than 100 MPa and fracture toughness of greater than 5 MPam^(½) and the metallic layer is a corrosion resistant metal such asstainless steel or titanium. The metal can also be, for example,titanium alloys, cobalt, chrome, cobalt-chrome alloys, nickel oraluminum. It is also preferable that the material be in the form of atape and that alumina be incorporated into at least one layer of thetape to provide a layer with high wear resistance. Several layers ofbioactive material in the form of thin tapes may be bonded together.Another aspect of the present invention is the use of the materialdescribed above in bone replacement procedures. The present invention isfurther directed to a process for making such compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Reproduction of a FTIR spectra for sintered (1000° C.) 45S5BIOGLASS® (brand of bioactive glass) discs: (a) unreacted and (b)reacted for 24 hours.

FIG. 2. Reproduction of a FTIR spectra for twice sintered (900° C. and1000° C.) 45S5 BIOGLASS® (brand of bioactive glass) discs after reactingfor 20 hours.

DETAILED DESCRIPTION OF THE INVENTION

Bioactive glasses in accordance with the present invention are anyglasses capable of forming hydroxycarbonate apatite, (HCA) afterexposure to simulated body fluids. Bioactive glasses include but are notlimited to melt-derived, ceramic, and sol-gel bioactive glasses. Forexample, such glasses may have the following compositional ranges:

SiO₂ 40-60 CaO 10-30 Na₂O 10-35 P₂O₅ 2-8 CaF₂  0-25 B₂O₃  0-10 K₂O 0-8MgO 0-5.

The preferred composition of the bioactive glass (BIOGLASS®) is:

SiO₂ 45 CaO 24.5 Na₂O 24.5 P₂O₅ 6

Metallic layers in accordance with the present invention may include allmetals typically used in biological applications such as titanium,titanium alloys, stainless steel, cobalt, chrome, cobalt-chrome alloys,aluminum, or nickel.

Tapes of bioactive glass in accordance with the present invention may beformed by casting. In the tape casting process, fine particles(typically 0.5-2.0 microns as measured by SEM or laser light scatteringtechniques) of bioactive glass, organic binder and plasticizers anddispersants are mixed to form a homogeneous slurry. The slurry is thenpoured onto a moving carrier film (i.e., polypropylene), forming aflexible tape by means of a doctor blade. The organic binder andplasticizer impart the tape with strength and flexibility. After drying,tapes of roughly 100 microns thickness are then peeled from the carrierfilm and laminated with tapes of similar or different composition toform a multi-layer bioactive material. Organic compounds are thenremoved prior to sintering. Addition of a thin, reinforcing, metalliclayer significantly improves the mechanical properties of multi-layer,bioactive materials.

A process in accordance with the present invention incorporates a metallayer into a bioactive multi-layer. This may be accomplished with tapecast technology. The bioactive layers may be tape cast and then themetal layers, or thin metal foils are laminated to the bioactivelayer(s) in the proper location for maximum toughness and strength. Thethickness of the metal layers should be at least 50 microns and aretypically no more than 200 microns. The metallic layers should remainductile, i.e., retain a strain-to-failure rate greater than about 3-8%at body temperatures. The layer should be near the surface in order toact as a crack arrestor. The outer layer can be any bioactive glassmaterial. The interlayers, which include metal and ceramic powders, aredesigned to produce an interface between the metal and bioactive layerwhich can be smooth, tortuous or intermediate between the two extremesin tortuosity.

Advantages of the present invention include the variation of thethickness and number of the metal layers, the method of bonding of themetal layer to the bioactive layer, the location of the metal layer withrespect to the surface and the selection of the materials. This processhas been designed for a broad range of materials. Any two chemicallycompatible bioactive/metal materials may be used. Preferably, bioactiveglass is the outer layer and a metal layer preferably includes titanium,stainless steel, aluminum or nickel. The subsurface layers can also bealumina, porous hydroxyapatite, zirconia, metal, porous alumina or anyother compatible, desired materials. Such composite material would havewide application in reconstructive surgery, especially where bonereplacement is indicated.

Ideally, the mechanical properties of the composite would match those ofnatural bone. Table I includes the mechanical properties of corticalbone. Metal layer reinforcement provides the added strength andtoughness necessary to match the flexural strength and strain to failureof bone. Metal selection involves the consideration of the conventionalmetals used as orthopaedic biomaterials, thermal expansion, oxidationstability, ability to be processed concurrently with bioactive glass,and availability. Table II lists the deciding factors for each metalsystem.

TABLE I Mechanical Properties of Cortical Bone Young's Modulus  6-20 GPaFlexural Strength 100-200 MPa Fracture Toughness  2-12 MPa m^(½) Strainto Failure  8%

TABLE II Reasons for Selecting Metal Systems Stainless Steel (316L)Titanium Orthopaedic material Orthopaedic material Relative oxidationresistance Biocompatibility Thermal expansion greater than bloactivelayer flakes commercially available 2 μm Powder available

Tape casting is a method that has been used commercially for theproduction of ceramic sheets for use in multilayer capacitors andsubstrates. It is currently being investigated as a method for producingstructural ceramics because the individual lamina are thin and hence,the maximum flaw size is only as large as the tape thickness. Theseadvantages, along with the possibility of producing complex shapes, maketape casting an attractive method for producing structural, bioactivematerial composites.

In the tape casting process, fine particles (preferably 0.5-2.0 microns)of bioactive glass, organic binder and plasticizers and dispersants aremixed to form a homogeneous slurry. Both attritor milling (4 hours, 400rpm) and ball milling (16 hours) are sufficient to reduce the initialbioactive glass particle size to that sufficient for tape casting. It isknown in the art that the quality and mechanical properties of sinteredceramics are influenced by the degree of homogeneity of the startingpowders. [ Reed, James S., Principles of Ceramics Processing, J. Wileyand Sons, Inc., NY, 1995.] The slurry is then poured onto a movingcarrier film (i.e. polypropylene), forming a flexible tape by means of adoctor blade. The organic binder and plasticizer impart the tape withstrength and flexibility. After drying, tapes of about 100 micronsthickness are then peeled from the carrier film and laminated with tapesof similar or different composition. Organic compounds are then removedprior to sintering.

Preparation of Composite Material

Preparation of the Bioactive Glass Slurry

Powdered bioactive glass, such as 45S5 BIOGLASS® (<125 μm) commerciallyavailable from U.S. Biomaterials Alachua, Fla., is milled using 34 mmZrO₂ media in denatured ethanol to a particle size distribution amenableto tape casting (0.2-20 μm). Slurries of bioactive glass are prepared bydissolving a polymer binder, e.g., polyvinylbutyral, and a plasticizer,e.g., phthalic acid, in a suitable solvent, preferably a polar, proticsolvent, e.g., an alcohol, an ester, an aromatic solvent, or mixturesthereof, such as 20% ethanol/80% toluene by weight. The bioactive glasspowder and ZrO₂ milling media are added and the slurry is mixed, e.g.for 12 hours. Table III shows the specific amount of each material to beused in the formation of the tape casting slurries.

TABLE III Standard Formula for Tape Cast Slurries Weight ComponentChemical %(Slurry) Powder BIOGLASS ® , Ti, or 20-80 316L, or Ti alloy orCo—Cr Binder Polyvinylbutyral (PVB)  2-12 Plasticizer Phthalic acid 0-6Solvent Toluene/ethanol 30-70

After mixing, the slurries are allowed to settle for about 15 minutes toallow air bubbles to escape prior to casting. Typically, tapes are castat a rate of about 1.0 ft/min to about 3.0 ft/min, e.g., 2.6 ft/min.Metal tapes and BIOGLASS®-metal tape preparation is carried out in thesame manner as described above.

It is desirable to have the maximum amount of powder in the slurry toachieve close packing of the glass or metal particles which will allowmore complete sintering. However, the viscosity of the slurry must besufficient for casting. Thinner tapes are also desirable so that thelargest flaws are relatively small. Therefore, the slurry composition isoptimized to achieve these goals.

Lamination

Circular shapes cut from the tapes (1-25″ diameter by about 100 μmthick) are stacked and cold pressed from to about 20 to 250 MPa and75°-200° C. for 10 to 15 minutes. A functionally gradient material canthen be formed using tapes containing mixtures of bioactive glass andmetal powder. For example, the composite may include a titanium innerlayer surrounded by 50/50 bioactive glass layers and covered with purebioactive glass surface layers. The interlayers between the metal andBIOGLASS ® can be a mixture of the two materials in order to control thegeometry and thermal expansion coefficient of the interface.

Binder Removal

Organic binding material can be removed between about 450° C. and about600° C. [Reed, James S., Principles of Ceramics Processing, J. Wiley andSons, Inc., NY, 1995.] Although a rapid burnout schedule is desired foreconomic reasons, slow burnout is more like to remove organicshomogeneously. The resulting powder compact is fairly fragile.

Differential thermal analysis (DTA) and thermogravimetric analysis (TGA)have shown that burnout is complete for an alumina tape between487.5-535° C. using a 10° C./min heating rate. This value will decreaseslightly at for the rate used for burnout (1° C/min). Organic materialscan be removed from 316L stainless steel laminates without excessiveoxidation occurring. Titanium is less oxidation resistant, but reductionin H₂ atmosphere is possible during hot pressing.

Sintering/Hot Pressing

Laminates may be hot pressed under vacuum or under specific (typicallyinert) atmosphere or sintered without pressure in air. Hot pressedsamples are processed in vacuum or under atmosphere using a die, e.g.graphite, and at a typical temperature and pressure of 1350° C. and 46MPa, respectively. During hot pressing, samples are covered withgraphite or tantalum sheets. During the first stage of hot pressing areducing atmosphere (4% H₂/Ar) may be introduced to remove any oxidewhich forms during binder removal.

Air-sintered samples may be processed in a furnace such as a Thermolyne(FA 1730) furnace (maximum operating temperature of 1093° C.) or itsequivalent. A schedule for bioactive glass, e.g., 45S5 BIOGLASS®,processing is shown in Table VI.

TABLE VI Sintering Schedule Stage Rate (° C./min) Plateau Temp (° C.)Hold (min) 1 1 1000 180 2 1  25 end

The glass transition temperature of bulk 45S5 BIOGLASS® is approximately550° C. and wetting occurs near 900° C. Differential thermal analysis(DTA) may be used to compare these values with those of particulate 45S5BIOGLASS® to assess the crystallization kinetics which are useful indetermining the hot press heating schedule.

Densification

Only minimal densification of ball milled bioactive glass (5-50 microns)occurs between 600° C. to 700° C. For good consolidation, the bioactiveglass must be processed at 800° C. or above. For example, 45S5BIOGLASS®tape thickness decreases by approximately 55% after burnout andsintering.

Bioactive glass discs pressureless-sintered in air between 900° to 1000°C. undergo significant crystallization. Samples subsequently hot pressedin vacuum (<10⁻³ torr) at 1000° C. for two hours at 30 MPa do notexperience further shrinkage or densification.

Thus, the bioactive glass in its as-laminated, amorphous form will have,at elevated temperature, a viscosity too low to be sintered concurrentlywith titanium and 316L stainless steel powder. Therefore (a) thebioactive glass composite must be held at elevated temperatures, e.g.,800-1000° C. during hot pressing under vacuum to allow forcrystallization prior to application of pressure during consolidation ofthe metal phase or (b) the bioactive glass layer must be sintered aloneprior to hot pressing to induce adequate crystallization so that it isunable to flow at the metal processing temperature and pressure or (c)the milled bioactive glass powder must be crystallized prior to tapecasting.

Bioactivity

The bioactivity, i.e., the ability to chemically bond to both bone andsoft tissue, was assessed in vitro by soaking the laminate compositematerial in simulated body fluid (SBF) followed by FTIR spectroscopicanalysis to determine the extent of hydroxyapatite formation on thebioactive glass surface. The SBF can be prepared by mixing sodiumchloride, sodium bicarbonate, potassium chloride, calcium chloride,dibasic potassium phosphate and magnesium chloride in de-ionized water[Filho, O. P. LaTorre, G. P. and Hench, L. L. (1996). “Effect ofCrystallization on apatite-layer formation bioactive glass 45S5, J.Biom. Mater. Res. 30, 509-514. Kokubo T, Kushitani, H., Sakka, S.Kitsugi, T., and Yamamuro, T. (1990). “Solutions able to reproduce invitro surface-structure changes in bioactive glass-ceramic A-W,” J.Biomed. Mater. Res. 24, 721-34.]

Table VII compares the ionic concentrations of SBF with that of bloodplasma.

TABLE VII Comparison of Ionic Concentrations of SBF and Blood Plasma(mM) Ion SBF Blood Plasmas Na⁺ 142.0 142.0 K⁺ 5.0 5.0 Mg²⁺ 1.5 1.5 Ca²⁺2.5 2.5 Cl⁻ 147.8 103.0 HCO₃ ⁻ 4.2 27.0 HPO₄ ²⁻ 1.0 1.0 SO₄ ²⁻ 0.5 0.5

Specifically, disks (1.1 cm diameter by 2-3 min thick) of the sinteredbioactive glass laminates to be tested are immersed 25.0 mL SBFpreheated to 37° C. Typically, the disks are hung in the center of a 30mL polyethylene bottle, or similar container, to maximize the availablesurface area. Tests are conducted after immersion from about 2 hours to8 weeks of immersion.

Referring to FIG. 1 (a), FIG. 1 (b), and FIG. 2. in a typical FTIR scanof bioactive glass soaked in SBF, hydroxyapatite peaks are located near550 and 610 cm⁻¹, whereas the peak near 450 cm⁻¹ is attributed to thehydrated silica layer which forms upon immersion. This silica peak near450 cm⁻¹ decreases as the hydroxyapatite layer grows. The in vitroability of the discs to form hydroxyapatite layers appears to be greaterwith increasing sintering temperature. The figures show FTIR scans forbioactive glass discs (l cm diameter by 2-3 mM thick) soaked insimulated body fluid for 0-24 hours. FIG. 1a shows the FTIR spectra forbioactive glass laminate sintered at 1000° C. for 3 hr prior tosubmersion in SBF. The spectra after 24 hours immersion is shown in FIG.1b. Hydroxyapatite peaks are seen at approximately 600 cm-1. Thegreatest bioactive response was observed for a bioactive glass samplesintered twice (900° and 1000° C. for 3 hours each).

The FTIR spectra for an unreacted bioactive glass disc hot pressed undervacuum closely resembled FIG. 1(a). Therefore it is hypothesized thatthe bioactive glass is not reduced under vacuum processing and retainsin vitro bioactivity.

Mechanical Properties Strength indentation methods (e.g., Vickersdiamond, 0.5 kg load) are used to determine the flexural strength andfracture toughness of the laminates by four point bend testing. Sampledimensions are determined by ASTM Standard C 1161-90 (1-5 mm thick, 2 mmwide, and 25 mm length). The inner span of the 4-point test apparatus is6.67 mm and the outer span 19.9 mm. Both the tensile and compressiveside of the sample are polished with diamond wheels. The tensile side isfurther polished with diamond paste. The tensile side corners are alsorounded to avoid stress concentrations. The sample is pre-indented witha diamond indentor. The samples are then loaded in a tensile testingmachine at a rate of 0.1 mm/min to fracture.

The bulk and true density of samples may be measured as function of theprocessing conditions (temperature, pressure and atmosphere) using gaspycnometry. Young's modulus may be determined using ultrasonic methods.Mechanical testing includes cutting and polishing samples, andperforming four point bend testing according to ASTM C 1161-90 [281].Strength data is analyzed using the Student's t test and/or thecombination of ANOVA and Fisher's least significant difference test.

Characterization

XRD was performed on as-received 45S5 BIOGLASS® powder and on twosintered samples (600 and 900° C.). Crystallinity was minimal in theas-received samples and increased with sintering temperature.

SEM analysis has revealed that significant porosity may develop bothwithin the bulk and on the surface of 45S5 BIOGLASS® discs sinteredat >900° C. A second high temperature sintering also tends to lead tomore pronounced porosity development. Pores may be as large as 100microns and tend to be rounded suggesting loss of volatiles. Asbioactivity testing has revealed, the discs are bioactive and thereforethe glass is not likely loosing Na+. Furthermore, the glass is initiallypored at 1300-1350° C. so the glass should remain stable at these lowertemperatures. The most likely source of loss is water present as OHgroups. FTIR spectroscopy has shown the presence of large OH peaks near3400 cm⁻¹ in tape cast laminates. Water may be lost continuously fromthe start of heating. However, as densification begins near 900-1000°C., the loss may only become noticeable at this temperature. Water maybreak apart Si—O—Si links, making the glass more amenable to forming HAon the surface, despite the high crystallinity of the 34S5 BIOGLASS®sintered at 900-1000° C.

The amount of crystallization in 45S5 BIOGLASS® laminates will bedetermined as a function of temperature so that the optimum processingconditions with 316L steel and titanium can be used.

The 316L stainless steel is quite oxidation resistant, however, burnoutdoes introduce some oxide onto the surface. Therefore, the steel isexpected to bond well with the 45S5 BIOGLASS® laminates to produce acomposite with high toughness. The higher thermal expansion coefficientof the steel will place the outer 45S5 BIOGLASS® layers in residualcompression which should further increase the apparent fracturetoughness. Titanium is the most challenging of the metals, because ofits high melting temperature of approximately 1670° C.

Three point bend testing (14 mm span, 0.1 mm/min loading rate) wasperformed on as processed beams sintered at 900° C. (3 hrs). The beamsare fractured by the application of a force in the center of the beam onone side while the beam is supported at the two ends on the oppositeside. The average fracture stress was 71 MPa (n=5) with a standarddeviation of 3.7. The 4 point bend results for a second batch of beamssintered at 900° C. were evaluated. The hardness was 2.8 GPa (Vicker'sindentation method). The density was 2.73 g/cc, as determined by gaspycnometry.

The laminate can be used for bone fracture fixation. Bone plates areused to hold ends of the bone in close proximity so that healing cantake place. Flat bone plates can easily be produced by tape castingmethods. Currently, bone plates are fabricated from metals or polymers,materials which are not bioactive. A bioactive material should aid thehealing response.

We claim:
 1. A bioactive composite materiel comprising an outer layer ofbloactive glass, an interlayer, and a layer of ductile metal, theinterlayer being intermediate to the outer layer of bioactive glass andthe layer of metal, wherein the composite is in the form of a tape. 2.The composite of claim 1, the interlayer having a coefficient ofexpansion between a coefficient of expansion of the bioactive glass anda coefficient of expansion of the ductile metal.
 3. The material ofclaim 1, wherein the composite material has a flexural strength equal toor greater than 100 MPA end fracture toughness of greater than S MPain^(½.)
 4. The material of claim 1, wherein the metal of the metalliclayer is stainless steel, titanium, titanium alloys, cobalt, chrome,cobalt-chrome alloys, nickel or aluminum.
 5. The material of claim 4,wherein the metal of the metallic layer is stainless steel.
 6. Thematerial of claim 1 wherein the interlayer is alumina, porous alumina,hydroxyapatite, metal, zirconia or mixtures thereof.
 7. The material ofclaim 1, wherein the bioactive glass is composed of the followingcompounds by percent weight: Compound Percent SiO₂ 40-60 CaO 10-30 Na₂O10-35 P₂O₅ 2-8 CaF₂  0-25 B₂O₃  0-10 K₂O 0-8 MgO  0-5.


8. The material of claim 7, wherein the compounds are combined in thefollowing proportions by percent weight: Compound Percent SiO₂ 45 CaO24.5 Na₂O 24.5 P₂O₅
 6.


9. A method of replacing bone material comprising contacting bone inneed thereof with the composite of claim
 1. 10. The composite materielof claim 1, wherein said composite is in the form of a multi-layeredtape.
 11. The material of claim 1, wherein the interlayer is alumina.12. The material of claim 1, wherein the layer of ductile metal has astrain-to-failure greater than about 3-8% at body temperatures.